RESUMEN
Primary renal hypouricemia (RHUC) is a rare autosomal recessive disorder with a mean duration of end-stage acute kidney injury (EIAKI) of 14 days. The pathogenesis of EIAKI in patients with RHUC remains unclear. Several hypotheses have been proposed, including those related to the renal vasoconvulsive effect and the elevating effect of xanthine oxidase (XO). The effect of xanthine oxidase (XO) is most often observed following strenuous anaerobic exercise, which is frequently accompanied by low back pain, nausea, and acute kidney injury (AKI). Consequently, we postulate that EIAKI could be prevented by avoiding strenuous exercise, thus preventing the onset and recurrence of EIAKI. In this paper, we present a case of recurrent EIAKI in a patient with RHUC and a mutation in the SLC2A9 gene.
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Lesión Renal Aguda , Ejercicio Físico , Defectos Congénitos del Transporte Tubular Renal , Humanos , Lesión Renal Aguda/etiología , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Adolescente , Masculino , Recurrencia , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Xantina Oxidasa , Cálculos Urinarios/genética , Cálculos Urinarios/etiología , Cálculos Urinarios/complicaciones , China , Mutación , Pueblos del Este de AsiaRESUMEN
Urinary infectious stones are challenging due to bacterial involvement, necessitating a comprehensive understanding of these conditions. Antibiotic-resistant urease-producing bacteria further complicate clinical management. In this study, analysis of urine and stone samples from urinary tract infection (UTI) patients revealed microbial shifts, gene enrichment in stones, and metabolic pathway disparities; antibiotic resistance gene trends were phylum-specific, urease-producing bacteria are at risk of acquiring AMR carried by Enterobacteriaceae under antibiotic, emphasizing potential AMR dissemination between them; Correlations of key pathogenic species in kidney stone and urine microbial communities highlight the need for targeted therapeutic strategies to manage complexities in UTIs; Stones and urine contain a variety of deleterious genes even before antibiotic use, and piperacillin/tazobactam better reduced the abundance of antibiotic resistance genes in stones and urine. The presence of diverse antibiotic resistance and virulence genes underscores challenges in clinical management and emphasizes the need for effective treatment strategies to mitigate risks associated with UTIs and urinary infectious stone formation. Ongoing research is vital for advancing knowledge and developing innovative approaches to address these urological conditions.
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Infecciones Urinarias , Factores de Virulencia , Infecciones Urinarias/microbiología , Infecciones Urinarias/tratamiento farmacológico , Humanos , Factores de Virulencia/genética , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Microbiota/efectos de los fármacos , Microbiota/genética , Farmacorresistencia Bacteriana/genética , Cálculos Urinarios/microbiología , Cálculos Urinarios/genética , Femenino , Masculino , Farmacorresistencia Microbiana/genéticaRESUMEN
Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas Facilitadoras del Transporte de la Glucosa , Hiperuricemia , Proteínas de Neoplasias , Transportadores de Anión Orgánico , Ácido Úrico , Xantina Deshidrogenasa , Humanos , Hiperuricemia/etiología , Hiperuricemia/metabolismo , Hiperuricemia/genética , Ácido Úrico/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Xantina Deshidrogenasa/metabolismo , Xantina Deshidrogenasa/genética , Xantina Deshidrogenasa/deficiencia , Animales , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/etiología , Defectos Congénitos del Transporte Tubular Renal/metabolismo , Cálculos Urinarios/etiología , Cálculos Urinarios/metabolismo , Cálculos Urinarios/genética , Errores Innatos del MetabolismoRESUMEN
To investigate the relationship between several factors and urinary stone as well as different stone compositions. To guide the diagnosis, treatment, and prevention of urinary stone recurrence. We used bidirectional Mendelian randomization to analyze the causal relationship between hypertension and urinary stones, diabetes and urinary stones, and body mass index (BMI) and urinary stones. We retrospectively analyzed the medical records of patients with urinary stones admitted to a tertiary care hospital in Chongqing, China, from July 2015 to October 2022. Patients were included when they were first diagnosed with urinary stones. The odds ratio of calculi on hypertension estimated by inverse variance weighted was 8.46 (95%CI: 4.00-17.90, Pâ =â 2.25â ×â 10-8). The stone composition analysis showed that there were 3101 (67.02%) mixed, 1322 (28.57%) calcium oxalate monohydrate, 148 (3.20%) anhydrous uric acid, 16 (0.35%) magnesium ammonium phosphate hexahydrate, 11 (0.24%) dicalcium phosphate dihydrate, 10 (0.22%) carbonate apatite, 8 (0.17%) L-cystine, 4 ammonium uric acid (0.09%), and 7 other stone types (0.15%). Mendelian randomization studies have proven that urinary stones may be a potential risk factor for hypertension, while there is no causal relationship between diabetes and stones, BMI, and stones. Our retrospective study has shown that urinary stone components are closely associated with sex, age, hypertension, diabetes, and BMI. It is reasonable to suspect that treating a single stone component is ineffective in preventing recurrence. We also found that the peak incidence of urinary stones was at the most active stage of most people's working lives.
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Índice de Masa Corporal , Hipertensión , Análisis de la Aleatorización Mendeliana , Urolitiasis , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Hipertensión/epidemiología , Urolitiasis/epidemiología , Urolitiasis/genética , Adulto , Factores de Riesgo , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Anciano , Cálculos Urinarios/genética , Cálculos Urinarios/epidemiologíaAsunto(s)
Mutación , Transportadores de Anión Orgánico , Defectos Congénitos del Transporte Tubular Renal , Humanos , Mutación/genética , Transportadores de Anión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Ácido Úrico/metabolismo , Cálculos Urinarios/genética , Proteínas de Transporte de Catión OrgánicoRESUMEN
Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.
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Lesión Renal Aguda , Defectos Congénitos del Transporte Tubular Renal , Rabdomiólisis , Cálculos Urinarios , Masculino , Adulto , Humanos , Ácido Úrico , Cálculos Urinarios/genética , Cálculos Urinarios/complicaciones , Cálculos Urinarios/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Lesión Renal Aguda/genética , Mutación , Rabdomiólisis/genética , Rabdomiólisis/complicacionesRESUMEN
Background: Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal relationship between the two remains inconclusive. Objective: This study aimed to assess the causal relationship between circulating lipids (Triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein A [APOA], apolipoprotein B [APOB] and Pure hypercholesterolaemia), lipid-lowering drugs (HMGCR [HMG-CoA reductase] inhibitors and PCSK9[Proprotein Convertase Subtilisin/Kexin Type 9] inhibitors) and the risk of urinary stones, using genetic data. Methods: Genetic instrumental variables (GIVs) for circulating lipids and lipid-lowering drugs were obtained from the UK Biobank and existing literature. Outcome data were extracted from a genetic association database with 3,625 urinary stone cases and 459,308 controls. Two-sample MR analysis, employing the TwoSampleMR software package in R 4.2.3, was conducted to assess the associations between multiple exposures. The primary outcome was determined using the inverse variance weighted (IVW) method for the causal relationship between exposure and outcome, while additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were utilized as supplementary analyses. Robustness of the Mendelian Randomization (MR) analysis results was assessed through leave-one-out analysis and funnel plots. Results: The MR analysis revealed a significant association between elevated TG levels per 1 standard deviation and the occurrence of urinary stones (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.000-1.003, P = 0.010). However, no significant association was observed between factors other than TG exposure and the risk of urinary stone occurrence across all methods(LDL-C: [OR], 1.001; 95% [CI], 1.000-1.003, P=0.132;HDL-C: [OR], 0.999; 95% [CI], 0.998-1.000, P=0.151;APOA:[OR] being 1.000 (95% [CI], 0.999-1.001, P=0.721;APOB: [OR] of 1.001 (95% [CI], 1.000-1.002, P=0.058;Pure hypercholesterolaemia: [OR] of 1.015 (95% [CI], 0.976-1.055, P=0.455) and lipid-lowering drugs (HMGCR inhibitors: [OR], 0.997; 95% [CI], 0.990-1.003, P=0.301 and PCSK9 inhibitors:[OR], 1.002; 95% [CI], 1.000-1.005, P=0.099). Conclusion: Our findings provide conclusive evidence supporting a causal relationship between an increased risk of urinary stones and elevated serum TG levels. However, we did not find a significant association between urinary stone occurrence and the levels of LDL-C, HDL-C, APOA, APOB, Pure hypercholesterolaemia and lipid-lowering drugs.
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Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Cálculos Urinarios , Humanos , Proproteína Convertasa 9 , LDL-Colesterol , Factores de Riesgo , Análisis de la Aleatorización Mendeliana , Hipolipemiantes/efectos adversos , Triglicéridos , HDL-Colesterol , Apolipoproteínas B , Cálculos Urinarios/genética , Apolipoproteínas ARESUMEN
Urinary stone disease is based on gene-environment interaction with an almost 50% heritability. Despite all efforts from exome-sequencing and genome-wide association studies, the genetic factors making up for observed heritability have been incompletely characterized. The study by Sadeghi-Alavijeh et al. leverages the invaluable resources of the 100,000 Genomes Project and the UK Biobank to identify heterozygous rare variants in the phosphate transporter SLC34A3 as a significant factor of urinary stone disease, challenging the traditional concept of Mendelian inheritance.
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Cálculos Urinarios , Urolitiasis , Enfermedades Urológicas , Humanos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Interacción Gen-Ambiente , Cálculos Urinarios/genética , Urolitiasis/genéticaRESUMEN
Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While stone disease is associated with lifestyle, genetic factors also strongly contribute. Common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder. Here, we investigated the extent to which rare genetic variation contributes to the unexplained heritability of USD. Among participants of the United Kingdom 100,000-genome project, 374 unrelated individuals were identified and assigned diagnostic codes indicative of USD. Whole genome gene-based rare variant testing and polygenic risk scoring against a control population of 24,930 ancestry-matched controls was performed. We observed (and replicated in an independent dataset) exome-wide significant enrichment of monoallelic rare, predicted damaging variants in the SLC34A3 gene for a sodium-dependent phosphate transporter that were present in 5% cases compared with 1.6% of controls. This gene was previously associated with autosomal recessive disease. The effect on USD risk of having a qualifying SLC34A3 variant was greater than that of a standard deviation increase in polygenic risk derived from GWAS. Addition of the rare qualifying variants in SLC34A3 to a linear model including polygenic score increased the liability-adjusted heritability from 5.1% to 14.2% in the discovery cohort. We conclude that rare variants in SLC34A3 represent an important genetic risk factor for USD, with effect size intermediate between the fully penetrant rare variants linked with Mendelian disorders and common variants associated with USD. Thus, our findings explain some of the heritability unexplained by prior common variant genome-wide association studies.
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Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc , Cálculos Urinarios , Urolitiasis , Enfermedades Urológicas , Humanos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Sodio , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , Cálculos Urinarios/genética , Urolitiasis/genéticaRESUMEN
The causality between the urinary sodium-potassium ratio and upper urinary calculi has not been clarified and easily affected by confounders. We performed two-sample and multivariable Mendelian randomization (MR) analysis to evaluate the potential causal role of the urinary sodium-potassium ratio in upper urinary calculi. Data of the urinary sodium-potassium ratio (N = 326,938), upper urinary calculi (N = 337,199), and confounding factors including BMI (N = 336,107), ever-smoke (N = 461,066), hypertension (N = 218,754), diabetes (N = 218,792), and alcohol intake frequency (N = 462,346) were obtained from the IEU OpenGWAS Project database. The inverse-variance weighted (IVW), weighted median, and MR-Egger methods were used to estimate MR effects. The MR-Egger intercept test, Cochran's Q test, MR-PRESSO, leave-one-out method, and funnel plot were used for sensitivity analysis. A causal relationship was found between the urinary sodium-potassium ratio and upper urinary calculi (OR = 1.008, 95% CI = 1.002-1.013, P = 0.011). FinnGen data supported this conclusion (OR = 2.864, 95% CI = 1.235-6.641, P = 0.014). The multivariable Mendelian randomization analysis result showed that after adjusting for the effects of five confounders, the urinary sodium-potassium ratio was still positively correlated with upper urinary calculi (OR = 1.005, 95% CI = 1.001-1.009, P = 0.012). This study demonstrated a positive causal association between the urinary sodium-potassium ratio and upper urinary calculi using MR analysis. Timely identification of changes in urine composition and dietary regulation of sodium and potassium intake could greatly reduce the incidence of future urinary calculi.
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Líquidos Corporales , Cálculos Urinarios , Sistema Urinario , Humanos , Cálculos Urinarios/epidemiología , Cálculos Urinarios/genética , Bases de Datos Factuales , PotasioRESUMEN
Uric acid is the end product of purine metabolism. Uric acid transporters in the renal proximal tubule plays a key role in uric acid transport. Functional abnormalities in these transporters could lead to high or low levels of uric acid in the blood plasma, known as hyperuricemia and hypouricemia, respectively. GLUT9 has been reported as a key transporter for uric acid reuptake in renal proximal tubule. GLUT9 mutation is known as causal gene for renal hypouricemia due to defective uric acid uptake, with more severe cases resulting in urolithiasis and exercise induced acute kidney injury (EIAKI). However, the effect of mutation is not fully investigated and hard to predict the change of binding affinity. We comprehensively described the effect of GLUT9 mutation for uric acid transport using molecular dynamics and investigated the specific site for uric acid binding differences. R171C and R380W showed the significant disruption of the structure not affecting transport dynamics whereas L75R, G216R, N333S, and P412R showed the reduced affinity of the extracellular vestibular area towards urate. Interestingly, T125 M showed a significant increase in intracellular binding energy, associated with distorted geometries. We can use this classification to consider the effect mutations by comparing the transport profiles of mutants against those of chemical candidates for transport and providing new perspectives to urate lowering drug discovery using GLUT9.
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Transportadores de Anión Orgánico , Cálculos Urinarios , Humanos , Ácido Úrico/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/química , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Cálculos Urinarios/genética , Mutación , Proteínas de Transporte de Membrana/genética , Transportadores de Anión Orgánico/genéticaRESUMEN
Objective Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dL, and the Uur/Ucr and Cur/Ccr were 0.56±0.14% and 45.7±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.
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Gota , Cálculos Urinarios , Masculino , Humanos , Femenino , Ácido Úrico , Microglobulina beta-2 , Gota/complicaciones , Gota/genética , Cálculos Urinarios/complicaciones , Cálculos Urinarios/genéticaRESUMEN
Hypouricemia is defined as a level of serum uric acid below 2 mg/dl. Renal hypouricemia is related to genetic defects of the uric acid tubular transporters urate transporter 1 and glucose transporter 9. Patients with renal hypouricemia can be completely asymptomatic or can develop uric acid kidney stones or acute kidney injury, particularly after exercise. Renal hypouricemia is especially challenging to diagnose in patients with acute kidney injury, due to the nonspecific clinical, hematochemical and histological features. No common features are reported in the literature that could help clinicians identify renal hypouricemia-acute kidney injury. Currently available guidelines on diagnosis and management of renal hypouricemia provide limited support in defining clues for the differential diagnosis of renal hypouricemia, which is usually suspected when hypouricemia is found in asymptomatic patients. In this paper we report a case of renal hypouricemia-acute kidney injury developing after exercise. We carried out a review of the literature spanning from the first clinical description of renal hypouricemia in 1974 until 2022. We selected a series of clinical features suggesting a diagnosis of renal hypouricemia-acute kidney injury. This may help clinicians to suspect renal hypouricemia in patients with acute kidney injury and to avoid invasive, costly and inconclusive exams such as renal biopsy. Considering the excellent outcome of the patients reported in the literature, we suggest a "wait-and-see" approach with supportive therapy and confirmation of the disease via genetic testing.
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Lesión Renal Aguda , Defectos Congénitos del Transporte Tubular Renal , Cálculos Urinarios , Humanos , Ácido Úrico , Lesión Renal Aguda/diagnóstico , Cálculos Urinarios/etiología , Cálculos Urinarios/genéticaAsunto(s)
Transportadores de Anión Orgánico , Defectos Congénitos del Transporte Tubular Renal , Cálculos Urinarios , Humanos , Mutación , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Cálculos Urinarios/genéticaRESUMEN
OBJECTIVES: Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. METHODS: A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese. RESULTS: Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. CONCLUSION: Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia.
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Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Cálculos Urinarios/genética , Femenino , Variación Genética , Genotipo , Humanos , Japón/epidemiología , Masculino , Defectos Congénitos del Transporte Tubular Renal/epidemiología , Cálculos Urinarios/epidemiologíaRESUMEN
INTRODUCTION: Urinary tract stone disease (UTSD) is seen with increasing frequency in children, and genetic, metabolic and environmental factors are known to play a role in its etiology. Since it is a genetically heterogeneous disease, we investigated the multigene panel and metabolic evaluation together. MATERIAL AND METHOD: Forty-eight pediatric patients that underwent surgery for UTSD and were followed up in the Department of Urology of Çukurova University Faculty of Medicine between March 2016 and July 2019 were included in the study. Children with known metabolic diseases were excluded.A detailed history was taken from each patient, and presence of a positive family history was questioned. Blood and urine samples were obtained, and metabolic evaluation was performed. In addition, 2 cc peripheral blood samples were collected from selected patients to perform DNA isolation at Çukurova University Adana Genetic Diseases Diagnosis and Treatment Center. The analysis of the obtained sequence data was performed. RESULTS: Of the 48 children included in the study, 29 (60.4%) were male and 19 (39.6%) were female. The mean age was 60 ± 50 (12-192) months. It was observed that 28 (58.3%) of the patients included in the study had a positive family history.As a result of the next-generation sequencing studies conducted with the multigene panel, a total of 21 clinically significant variants in eight different genes were identified with the bioinformatics analysis on the data on which quality control was performed. The weighted distribution of the 21 variants according to the genes was as follows: five variants (23.8%) in the SLC3A1 gene, four (19%) in SLC6A20, and three (14.3%) in SLC7A9 and SLC26A1. The clinical reporting of the disease etiology and/or variants with prognostic significance determined as a result of the performed analyses was completed by field experts in accordance with international standards. The visuals of the detected variants are presented in Summary figure. CONCLUSION: In pediatric cases with UTSD, it is important to determine the underlying metabolic and genetic risk factors in order to prevent recurrence and apply the most effective treatment.
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Enfermedades Metabólicas , Cálculos Urinarios , Urolitiasis , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteínas de Transporte de Membrana , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/etiología , Recurrencia , Factores de Riesgo , Cálculos Urinarios/etiología , Cálculos Urinarios/genética , Adulto JovenRESUMEN
PURPOSE: Cystine stones are widely considered hard and difficult to treat. Hounsfield Units (HU) are used in other stone types to estimate 'hardness' and treatments based on that finding. Our objective was to report mean HU of cystine stones in vivo in a large case series of cystinuria patients and assess for differences in genotype. METHODS: A prospective case series of cystinuria patients referred to a specialist centre was analysed. CT imaging was assessed by two independent radiologists to determine in vivo attenuation of cystine calculi. Mean HU was compared for both cystinuria genes (SLC3A1 and SLC7A9) using an independent t-test. RESULTS: 164 adult cystinuric patients were identified (55% male), median age 43 years (range 18-80). Median follow up was 31 months (IQR 10-62). Genetic data available for 153/164 (93%) demonstrated 97 SLC3A1 (63%) and 55 (36%) SLC7A9 mutations (39 homozygous, 16 heterozygous) and one heterozygous for both SLC3A1/SLC7A9. 107 patients had CT images available demonstrating calculi. Median HU across the cohort was 633 (5th to 95th centile 328-780). There was no difference in mean HU between SLC3A1 and SLC7A9 genotypes (p = 0.68) or homo and heterozygous SLC7A9 (p = 0.70). Mean HU correlated with stone size (Pearson correlation coefficient = 0.51, p < 0.001). CONCLUSION: In this large single centre cystinuria cohort, mean HU was low for stones that are difficult to treat. Calculi of < 800 HU should prompt consideration of a cystinuria diagnosis. Attenuation was not associated with genotype, and distinct 'smooth' and 'rough' stones were not observed. Calculi with HU > 1000 are unlikely pure cystine, and in a known cystinuric would suggest conversion to another stone type.
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Cistinuria/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Cálculos Urinarios/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Medios de Contraste , Cistinuria/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodos , Cálculos Urinarios/genética , Adulto JovenRESUMEN
Calcium oxalate stones are closely related to oxalate metabolism and oxidative stress injury. Normal metabolism homeostasis and tissue repair are often affected by the biological rhythm, which plays an indispensable role in maintaining the homeostasis of the organism. Nuclear factor erythroid 2-related factor/heme oxygenase-1 (NRF2/HO-1) is one pathway related to oxidative stress injury in human body. Normal operation of this pathway is conducive to the resistance against oxidative stress-related injury. This study was mainly aimed to explore whether the rhythm gene "brain and muscle ARNT-like 1" (BMAL1) was involved in regulating oxidative stress-related NRF2/HO-1 pathway to reduce the formation of urinary calcium oxalate stones. In vitro experiment found that the activation of NRF2/HO-1 can significantly reduce the oxalate-induced oxidative damage and urinary calcium oxalate stone formation, and the relative expression of BMAL1 was increased. Then overexpression of circadian gene BMAL1 can activate the NRF2/HO-1 pathway and reduce the oxalate-induced oxidative damage. In the hyperoxaluria animal model, the BMAL1 expression level decreased obviously, and the production of calcium oxalate stones was significantly reduced after activating NRF2/HO-1. Finally, we further verified the BMAL1 expression in blood samples from the patients, and analysis of several single nucleotide polymorphisms showed BMAL1 was related to calcium oxalate stones. Therefore, maintaining normal biorhythms and appropriately intervening related rhythm genes and their downstream antioxidant pathways may play an important role in the prevention and postoperative recurrence of urinary calcium oxalate calculi, which may open up new directions for the treatment of urinary calculi.